Gout arises from purine metabolism disorder in the body and building up of excess uric acid in blood, causing precipitation of urate in joints, kidneys and connective tissues, leading to gouty arthritis, gouty neuphropathy, urolithiasis, etc., medically referred to as gout. The disease is characterized by the presence of birefringent sodium monohydrate crystals in synovial fluid and tophi. Its clinical features include hyperuricemia and urate crystals, characteristic acute arthritis, tophi and interstitial nephritis resulted from deposition, joint deformity and dysfunction in severe cases, usually accompanied by uric acid urolithiasis, which is mostly found in obese middle-aged and elderly males and postmenopausal females.
Medicaments for treatment of gout are divided into 3 classes according to their functional characteristics:
The first class would be antigout drugs including indomethacin and colchicine tablets.
Indomethacin has a mild uricosuric effect that relieves pain arising from gout attacks. It is often used in bone joint diseases caused by gout. This drug, which are not suitable for long-term use, must be swallowed whole, and individuals with gastric ulcer, epilepsy and mental disorders are prohibited from this drug.
Colchicine tablets have relatively larger toxic adverse effects, and its use is currently limited to acute gout attack. Some patients experience reactions such as vomiting and diarrhea after administering this drug and the optimal dose of colchicine against gout requires further study.
The second class would be uricosuric drugs. Probenecid belongs to this class of drugs. Its main function is to suppress urate reabsorption by renal tubules so as to increase urate excretion and decrease urate concentration in blood to prevent formation of urate crystals and improve joint function. This drug also promotes dissolution of existing urate crystals. The drug has no anti-inflammatory and analgesic effects, and is generally administered for treating chronic gout or during gout recovery.
The third class would be inhibitors of uric acid synthesis.
Allopurinol belongs to this class of drugs. Its main function is to prevent hypoxanthine and xanthine in the body from metabolizing into uric acid by inhibiting xanthine oxidase so as to reduce uric acid formation. It can be administered to treat primary, secondary and chronic gouts. This drug cannot control acute inflammation during gout attacks, and can only be administered approximately two weeks after the acute phase of gout resolved.
Uric acid is a result of xanthine oxidation. Uric acid metabolic disorders include, but are not limited to diseases related to abnormality of uric acid metabolism such as polycythemia, myeloid metaplasia, gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular diseases, coronary heart diseases, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, renal diseases, nephrolithiasis, renal failure, joint inflammatory disorders, arthritis, urolithiasis, lead poisoning and sarcoidosis.
Lesinurad is an orally administered effective URAT1 inhibitor. Results from phase-1 and 2 clinical trials show that, when used in combination with xanthine oxidase inhibitors, Lesinurad can effectively modulate uric acid levels, and has higher levels of safety. Its structural formula is shown below:

Lesinurad has problems such as low pharmacodynamic activity, large dosage and high nephrotoxicity and development of URAT1 inhibitors with higher therapeutic efficacy is needed. The present invention provides an antigout drug having improved therapeutic effect based on the discovery of a series of benzimidazole and their derivatives exhibiting good URAT1 inhibitory effects which outperform Lesinurad during in vitro screening and pharmacological studies.